Showing posts with label GS-5885. Show all posts
Showing posts with label GS-5885. Show all posts

Wednesday, May 15, 2013

Hepatitis C Therapy Update 2013-What About Interferon-free Regimens?

Hepatitis C Virus Therapy Update 2013

Lisa C. Casey, William M. Lee

Curr Opin Gastroenterol. 2013;29(3):243-249.

Medscape Today

Abstract and Introduction

Purpose of review: We review here the recent literature regarding hepatitis C virus (HCV) therapy through January 2013. We discuss current therapies, targets for new therapies, and what might be expected in this rapidly changing field.

Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.

Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.

An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.[4]
Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al. [8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.[4,10]
Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.

Viral Structure
What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.

Figure 1.

Viral structure and genome demonstrating potential therapeutic targets. Reproduced with permission from.[12] HCV, hepatitis C virus.

The Era of Triple Therapy
The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward.

First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir
Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.[14–17]
Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.

Limitations of First-generation Direct-acting Antiviral Therapy
Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.[22]

What is Needed: Goals for the Future
Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.
Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.

Understanding Direct-acting Antiviral Resistance is Important for the Future
Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.

Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.

New Drugs in Development
In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development

Table 1.  New hepatitis C drugs in development
NS3/4A protease inhibitorsNS5ANS5B polymerase nucleos(t)ideNS5BNNI Host targets
MK-5172PPI-461PSI-938VX-222lambda IFN

Protease Inhibitors: The Next Generation
Despite their limitations, protease inhibitors have high antiviral efficacy and will play an important role in future therapies. Newer protease inhibitors in development: asunaprevir, danoprevir, vaniprevir, MK-5172, BI-201335, and simeprevir are expected to have improved tolerance and safety profiles and will likely be used in combination with pegylated interferon and ribavirin or in newer DAA combination regimens in the future.

Polymerase Inhibitors: NS5B
Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Their success has been demonstrated extensively in phase 1 and 2 trials, and they are expected to play an important role in newer DAA combination therapy regimens. The class comprises two types – nucleos(t)ide inhibitors and non-nucleotide inhibitors (NNIs). Nucleos(t)ide analogue inhibitors are active site inhibitors that mimic the natural substrates of the polymerase, being incorporated into the RNA chain and causing direct chain termination. As the active site of NS5B is highly conserved, these are potentially active against all the different genotypes. In addition, as amino acid substitutions in every position of the active site may result in loss of function, resistance to nucleos(t)ide analogue inhibitors is usually low. Mericitabine and sofosbuvir both have demonstrated convincing data in clinical trials.
Non-nucleoside inhibitors, on the contrary, bind to several discrete sites outside of the polymerase active center, which results in a conformational protein change before the elongation complex is formed – essentially inhibiting the polymerase from a distance. Resistance is more frequent with NNIs as NS5B is structurally organized into multiple different domains with at least four different binding sites. Mutations at the individual binding sites do not necessarily cause loss of function of the polymerase.[25] Drugs in this category are tegobuvir, filibuvir, BI-207127, VX-222, ANA598, ABT-333.

NS5A Inhibitors
NS5A is a membrane-associated phosphoprotein involved in HCV virion production and the viral life cycle. Daclatasvir, the first in its class NS5A inhibitor, exhibits high potency and is expected to have a broad range of genotypic coverage; it is synergistic with other DAAs. Several others are in development including ABT-267, GS-5885, PPI-461.[25,28]

Host-targeted Therapies
Several drugs are in development against host targets. Cyclophilin inhibitors such as the cyclophilin A binding molecule alisporivir appear to have potent anti-HCV activity and have broad genotype activity for types 1–4. Alisporivir appears to inhibit HCV viral replication by interfering with the interaction between cyclophilin A and NS5A. In early trials with pegylated interferon and ribavirin, an SVR rate into the 70% range was seen with 24 weeks of once daily therapy and benefits have been confirmed in genotypes 2 and 3, with particular success against genotype 3 and a very high barrier to resistance.[23] An additional host-targeted agent is the subcutaneously administered drug, mirvirsen, which specifically targets the liver-specific micro-RNA miR-122 that is involved in gene expression and HCV viral replication, producing dramatic suppression of HCV viremia without evidence of RAV or significant side effects in early trials. New interferons have also been explored. Native human interferon lambda proteins are generated by the immune system in response to viral infection. This interferon family has been found to have antiviral activity against HCV. The interferon and its receptor are both expressed at high levels by hepatocytes but not all tissues suggesting that this reagent could have tissue specific effects, potentially equating to reduced toxicity compared to current experience with α-interferon.[23] This could be a better tolerated alternative to interferon α until oral regimens are available.

What About Interferon-free Regimens?
Interferon-free regimens are widely being tested in clinical trials with encouraging results. The following selected trials demonstrate how rapidly progress is being made. Beginning in 2010, studies demonstrated the potential for antiviral efficacy of an all-oral regimen using combinations of drugs with different targets.

Interferon-free regimen for the management of HCV-1 (INFORM-1) was a phase 1 proof of concept study from 2010 using combination DAA without interferon.[27] Danoprevir, an NS3/4A protease inhibitor, and RG7128 (later named mericitabine), a NS5B nucleoside polymerase inhibitor, were given for up to 13 days in multiple different dosing arms to assess the ability of an interferon-free regimen to suppress viral load. After the treatment period, all patients subsequently were given standard of care pegylated interferon and ribavirin for 48 weeks. Overall, the DAA combination therapy was well tolerated, and there were no treatment-related study withdrawals or dose reductions during the treatment period. Most common adverse event was headache. The DAA combination regimen showed very potent activity against HCV in all participants, including previous null responders giving encouragement that interferon-free all DAA regimens are possible. Of note, patients with cirrhosis were excluded.

SOUND-1 and SOUND-2 trials included an NS3/4A protease inhibitor (BI-201335) and an NNI NS5B polymerase inhibitor (BI-207127) and ribavirin to demonstrate proof of potent antiviral activity against HCV with rapid viral response rates of 73–100% dependent on dosing. Genotype 1b responded more favorably than 1a and the ribavirin-sparing arm in the later trial showed reasonable but substantially lower response rates. Final results were presented in abstract form at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2012.[29] Patient results were randomized by genotype 1a versus 1b and by IL-28 genotype CC/CT/TT. Ribavirin arms with variable DAA dosing demonstrated a range in SVR12 (SVR after only 12 weeks off therapy), of 52–69% but only 39% in ribavirin-free arms. Genotype 1b responded better than 1a and IL-28 appeared to be an independent predictor of SVR. All IL-28 genotype of 1b and IL-28 CC 1a patients demonstrated SVR 12 rates as high as 84% with the all-oral regimen.

More recently, exciting results from the phase 2 ELECTRON trial were reported.[30] Sofosbuvir (formerly known as GS-7977) NS5B polymerase inhibitor in a once daily dose was combined with ribavirin for 12 weeks, pegylated interferon and ribavirin for 4, 8, or 12 weeks in naive patients with genotypes 2 or 3 or sofosbuvir monotherapy for 12 weeks in naive patients with genotypes 2 or 3. An additional group of 35 genotype 1 patients was enrolled, 25 naive patients and 10 prior nonresponders who were also treated with sofosbuvir and ribavirin for 12 weeks. After 24 weeks of therapy, all naive genotype 2 and 3 patients on combination therapy had an SVR at 24 weeks (100%). SVR was seen in only 60% of the genotype 2 and 3 patients on monotherapy. Among genotype 1, treatment-naive patients demonstrated 84% SVR and prior nonresponders fared less well with an SVR of only 10%. Sofosbuvir appears to be well tolerated and to have a high barrier to resistance. This study suggests a new DAA option may soon be available for naive patients with genotype 1, 2, and 3; however, ribavirin still plays a role in maintenance of an antiviral response.[30]
Another new phase 2 clinical trial was found to show even better responses in genotype 1 patients. ABT-450 (an NS3 protease inhibitor) combined with low-dose ritonavir, ABT-333 (a non-nucleoside NS5B polymerase inhibitor), and ribavirin were used in varying doses in treatment-naive and experienced patients excluding those with cirrhosis for 12 weeks. Treatment-naive patients demonstrated an SVR12 of 93–95% depending on dose and treatment experienced patients an SVR12 of 47%. Some viral breakthrough and resistance was noted during treatment in the prior nonresponder population and the study suggests this population will need a modified DAA regimen as extending duration would not have changed outcome. Overall, this 12-week combination therapy may be an effective future therapy for HCV genotype 1.[31]

We are once again preparing for a dramatic paradigm shift in approach to HCV infection. Worldwide, the epidemic proportions of HCV are coming to light both in the efforts of healthcare workers and governments in the underdeveloped world and in the burden from untreated and undiagnosed disease in the developed world. Numerous new drugs targeting various aspects of the HCV life cycle and the host are in development and clinical trials. Overall, combination therapies will be the rule. New combinations of DAA have synergistic effects, decrease the risk of resistance, and improve antiviral efficacy, are effective in different genotypes and have a favorable safety profile. Despite universal hope for all-oral regimens, pegylated-IFN is still in the literature. Many phase 1 and 2 clinical trials are still designed to demonstrate the safety of new DAA in combination with a pegylated interferon and ribavirin backbone and though the best response rates in interferon containing regimens still tend to be in favorable genotypes or IL-28 CC patients, the important benefit in these combinations is much shorter treatment duration of 12 weeks. Interferon-free combination regimens appear to be on the horizon, providing a new option in particular for patients with non-genotype 1 HCV, but there will still be treatment failures and resistance issues to be overcome, particularly in the treatment experienced population.

Monday, April 29, 2013

EASL 2013: 'Quad' HCV Tx Works but No More Trials Planned

'Quad' HCV Tx Works but No More Trials Planned

By Michael Smith, North American Correspondent, MedPage Today
Published: April 29, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – A four-drug regimen was effective in hard-to-treat hepatitis C (HCV) patients who had previously failed therapy, a researcher said here, but the drug combination is not being further developed.

Action Points
  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • The combination of an NS5A inhibitor, a protease inhibitor, and pegylated interferon plus ribavirin appeared to be effective in treatment experienced, genotype 1 HCV-infected patients.

    In a phase II study, 70% of patients had undetectable HCV virus 12 weeks after ending the so-called "quad regimen," according to Gregory Everson, MD, of the University of Colorado in Aurora.

    The drug protocol consisted of an NS5A inhibitor dubbed ledipasvir and a protease inhibitor, GS-9451, along with pegylated interferon and ribavirin.

    Among those who responded to the four-drug regimen quickly and persistently, the rate was even higher at 87%, Everson reported at the meeting of the European Association for the Study of the Liver.

    But despite the promise of what he called a "re-treatment protocol," Everson said further development of the regimen is not in the cards.

    He did not immediately respond to an email from MedPage Today seeking clarification, but other experts here suggest it may have to do with the perception that pegylated interferon and ribavirin are on the way out.

    Meanwhile, ledipasvir and GS-9451 remain in clinical development, according to a spokesman for the developer, Gilead Sciences of Forest City, Calif.

    The results of the trial "are not entirely unexpected," commented Heiner Wedemeyer, MD, of Hannover Medical School in Hannover, Germany, who was not involved with the study.

    "This specific regimen is not being further developed," he said, but what investigators "learned is that if we add more potent drugs, we can treat more difficult patients. We confirmed that concept."

    It seems likely, he said, that the two drugs will continue to be developed for use without interferon and perhaps ribavirin. "The question will be whether we can shorten treatment," Wedemeyer said.

    Until 2011, standard therapy for HCV genotype 1 was 48 weeks of pegylated interferon with ribavirin, a regimen regarded as difficult to tolerate with a substantial proportion of treatment failures.

    Current standard therapy adds a third drug, one of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis), but those medications have their own side effects and risks.

    Patients who fail standard treatment – either relapsing or not responding in the first place – need better options, Everson said here.

    He and colleagues tested the four drugs (ledipasvir, GS-9451, pegylated interferon, and ribavirin) in a response-guided fashion, enrolling 163 patients, including 52 who had not responded to previous therapy, 28 who had a partial response, and 83 who either relapsed or had viral breakthrough on treatment.

    Patients who had undetectable viral RNA at weeks four through 20 of treatment stopped therapy after 24 weeks, while the others stopped ledipasvir and GS-9451 but continued the other two drugs for another 24 weeks.

    The 70% rate of undetectable virus 12 weeks after the end of therapy (SVR12) indicated a "fairly robust antiviral effect," Everson said, and response during therapy was "highly predictive " of treatment success.

    Among those who had a so-called extended rapid virologic response – no detectable virus from weeks four through 20 – the SVR12 rate was 87%, compared with just 28% among those who did not have such a response.

    Everson said that patients with genotype 1b did better than those with genotype 1a, while those with the favorable CC variant of the IL-28B gene did better than those with other versions.

    He added that 5% of patients had a serious adverse event during the study and 7.3% stopped treatment because of adverse events, all attributed to the interferon or ribavirin.

    The overall pattern of adverse events, he said, was "typical" of what is seen with the two older drugs.

    The study was supported by Gilead. Everson reported financial links with the company as well as BMS, Abbott, Roche/Genentech, Vertex, Merck/Schering-Plough Novartis, Janssen/Tibotec, GSK, Eisai, and BioTest.

    Wedemeyer reported financial links with Abbott, Achillion, Biolex, BMS, Gilead, Janssen-Cilag, Merck, Novartis, Roche, Siemens, Transgene, and ViiV.

    Primary source: European Accociation For the Study of the Liver
    Source reference:
    Everson GT, et al "Combination of the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis C infection" EASL 2013; Abstract 13.

  • EASL Conference Coverage @ MedPage Today

    Drug Trio Helps Treat HCV After Transplant
    AMSTERDAM -- Three-drug therapy appears to help liver transplant patients whose hepatitis C (HCV) recurs, a researcher said here. 
    AMSTERDAM -- High levels of hemoglobin may be dangerous in patients with non-alcoholic fatty liver disease (NAFLD), with bleeding a potential remedy, researchers said here. 

    Saturday, April 27, 2013

    EASL 2013 Highlights - CCO's independent conference coverage

    Program Overview
    2013 Annual Meeting of the European Association for the Study of the Liver*
    April 24-28, 2013 | Amsterdam, The Netherlands
    CCO's independent conference coverage of the 2013 Annual Meeting of the European Association for the Study of the Liver includes 2 CME-certified slidesets with faculty analysis and downloadable slidesets that focuses on key issues highlighted at the conference.
    **Free registration required
    Latest Content
    Daclatasvir Plus Asunaprevir Plus BMS-791325 Achieves ≥ 88% SVR Rates in Noncirrhotic Treatment-Naive Patients With Genotype 1 HCV
    The all-oral regimen combining an NS5a inhibitor, a protease inhibitor, and a nonnucleoside polymerase inhibitor was well tolerated at both doses of BMS-791325 studied.
    Date Posted: 5/3/2013

    HBV DNA Seroclearance Significantly Reduces Risk of HCC in Patients With High Baseline Viral Loads
    Seroclearance of HBeAg, HBsAg did not significantly decrease HCC risk in adjusted analysis.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/2/2013

    CONCISE: Interim Results Show High SVR Rates With Either 12 or 24 Weeks of Telaprevir Plus Peginterferon/Ribavirin in Patients With HCV Genotype 1 and IL28B CC Genotype
    Among patients who completed 12 weeks of triple therapy, 100% SVR12 rate among patients who continued to receive peginterferon/ribavirin through 24 weeks vs 89% SVR4 rate among patients who stopped all therapy at 12 weeks.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/2/2013

    QUEST-1: Simeprevir Plus PegIFN/RBV Significantly Improves SVR12 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 1 HCV
    Triple therapy was well tolerated and 85% of patients were able to shorten treatment to 24 weeks, of whom 91% achieved SVR12.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/1/2013

    COMMAND: Daclatasvir Plus PegIFN/RBV Improves SVR24 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 2/3 HCV
    The triple-drug regimen allowed 83% of patients to receive shorter treatment durations of only 12 or 16 weeks, and safety and tolerability was comparable to pegIFN/RBV alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    QUEST-2: Simeprevir Plus PegIFN/RBV Superior to PegIFN/RBV for SVR12 in Treatment-Naive Patients With Genotype 1 HCV
    Triple therapy was well tolerated and enabled most patients (91%) to shorten the duration of therapy to 24 weeks while maintaining a high SVR12 rate of 86% in this subgroup.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    POSITRON: Sofosbuvir/Ribavirin Superior to Placebo With 78% SVR12 Rate in Genotype 2/3 HCV–Infected Patients Intolerant of, Ineligible for, or Unwilling to Receive IFN
    Sofosbuvir plus ribavirin is a safe, effective, IFN-free alternative for patients chronically infected with genotype 2/3 HCV who have no other treatment options available.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Observed HCC Incidence Lower Than Predicted in Patients With Chronic Hepatitis B Receiving Tenofovir in Phase III Clinical Trials
    The effect of tenofovir was more noticeable in noncirrhotic patients, emerging at 2 years of treatment and reaching statistical significance by 6 years of treatment.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Prolonged Tenofovir-Based Antiviral Therapy Maintains HBV DNA Suppression in Patients With Chronic HBV, Normal ALT Levels, and High HBV DNA Levels
    HBV DNA suppression was increased with tenofovir plus emtricitabine vs tenofovir alone, but safety profiles of both regimens were favorable through 192 weeks of study.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
    In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013

    FISSION: Sofosbuvir/Ribavirin Noninferior to Peginterferon/Ribavirin for SVR12 in Treatment-Naive Patients With HCV Genotype 2/3
    Efficacy was similar between the 2 treatment arms, but sofosbuvir/ribavirin demonstrated superior safety and tolerability with shorter therapy compared with peginterferon/ribavirin.
    Date Posted: 4/28/2013
    NEUTRINO: Sofosbuvir Plus Peginterferon/Ribavirin Achieves High SVR12 Rate, Well Tolerated in Treatment-Naive Patients With Genotype 1, 4, 5, or 6 HCV
    The triple-therapy regimen yielded 90% SVR12 in the overall population, and all patient subgroups attained at least 80% SVR12 rate, including patients with cirrhosis and those with IL28B non-CC genotype.
    Date Posted: 4/28/2013

    FUSION: Sofosbuvir/Ribavirin Superior to Historical Controls for SVR12 in Treatment-Experienced Patients With Genotype 2/3 HCV
    Significantly better rates of SVR12 with both 12 and 16 weeks of therapy compared with historical controls, with better outcomes with 16 weeks of therapy among patients with genotype 3 HCV
    Date Posted: 4/28/2013
    STARTVerso1: Faldaprevir Plus Peginterferon/Ribavirin Highly Effective, Well Tolerated in Treatment-Naive Patients Infected With Genotype 1 HCV
    Most patients receiving faldaprevir (88%) were able to shorten therapy to 24 weeks total, without compromising sustained virologic response, which was 88% in this subgroup.
    Date Posted: 4/28/2013 

    Daclatasvir Plus Sofosbuvir ± Ribavirin Achieves 95% to 100% SVR12 Rate in Patients With Previous Virologic Failure on Telaprevir or Boceprevir            
    Virologic response rates to all-oral, once-daily 24-week regimen unaffected by baseline NS3 variants conferring protease inhibitor resistance
    Date Posted: 4/28/2013

    QUANTUM: Interferon-Free Sofosbuvir/Ribavirin Regimen Achieves 52% to 72% SVR12 Rate in Treatment-Naive Patients With Chronic HCV Infection
    QUANTUM also identified marked elevations in ALT and/or AST associated with the guanidine nucleotide analog GS-0938, which resulted in GS-0938—containing arms being halted.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013
    Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
    In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013

    AVIATOR: ABT-450/Ritonavir, ABT-267 and/or ABT-333, and RBV Achieves SVR24 Rates ≥ 90% in Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
    The 4-drug peginterferon-free regimens also yielded SVR rates ≥ 89% in treatment-naive patients and previous null responders regardless of sex, HCV subtype, baseline HCV RNA, IL28B genotype, and fibrosis severity.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/26/2013

    High Rate of Advanced Fibrosis in Patients With HBV/HIV Coinfection, Despite HBV Suppression With Antiretroviral Therapy
    Patients with HBV/HIV coinfection treated with HBV-suppressing antiretrovirals continue to demonstrate high rates of advanced fibrosis.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/26/2013

    ELECTRON: Addition of Second DAA to Sofosbuvir and Ribavirin Yields Rapid, Sustained Antiviral Suppression in Both Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
    Combining ledipasvir with sofosbuvir/ribavirin yielded SVR12 rates of 100% in both treatment-naive patients and previous null responders, lending further support to ongoing development of the sofosbuvir/ledipasvir fixed-dose combination tablet.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver

    Monday, October 8, 2012

    October Hepatitis C Clinical Trial Updates From

    Article Of Interest - Creative Marketing, Clinical Trials, and You
    What began as a lovely morning abruptly ended with a confusing press release describing a new clinical trial for hepatitis C. It seemed less like a notification of a new drug trial and more like an instrument of marketing.....

    A service of the U.S. National Institutes of Health Hepatitis C - updated in the last 30 days

    The HCV clinical trials on this page are not a complete list; to learn more about Hepatitis C virus clinical trials or to find out if a study is enrolling patients in your area, please click here.

    Evaluation of Safety Tolerability and Antiviral Activity of ACH-0143102 Plus RBV Treatment Naive HCV GT1b Subjects 
    ‎Tuesday, ‎October ‎02, ‎2012, ‏‎9:00:00 AM
    Condition: Chronic Hepatitis C Infection
    Interventions: Drug: ACH-0143102; Drug: Ribavirin
    Sponsors: Achillion Pharmaceuticals; Achillion Pharmaceuticals
    Recruiting - verified October 2012

    Safety and Efficacy of Sofosbuvir/GS-5885 Fixed-Dose Combination (FDC) +/-Ribavirin for the Treatment of HCV 
    ‎Tuesday, ‎October ‎02, ‎2012, ‏‎9:00:00 AM
    Condition: Chronic Hepatitis C Virus
    Interventions: Drug: Sofosbuvir/GS-5885 400/90 mg; Drug: Ribavirin
    Sponsors: Gilead Sciences; Gilead Sciences
    Recruiting - verified October 2012

    An Open-Label Study of the Effect of Telaprevir in Combination With Peginterferon Alfa-2b and Ribavirin in Pediatric Subjects Infected With HCV 
    ‎Thursday, ‎September ‎27, ‎2012, ‏‎9:00:00 AM
    Condition: Hepatitis C
    Interventions: Drug: Telaprevir; Drug: Peginterferon alfa-2b; Drug: Ribavirin
    Sponsors: Vertex Pharmaceuticals Incorporated; Vertex Pharmaceuticals Incorporated
    Not yet recruiting - verified October 2012

    Randomized Controlled Open Label Trial of Peg Alpha 2a Interferon and Adjusted-dose of Ribavirin vs. Standard Therapy in the Treatment of Naive Chronic Hepatitis C Patients Infected With Genotype 4 
    ‎Thursday, ‎September ‎13, ‎2012, ‏‎9:00:00 AM
    Condition: Chronic Hepatitis C Virus
    Intervention: Drug: Pegylated interferon alpha-2a
    Sponsors: King Abdulaziz Medical City; King Abdulaziz Medical City
    Recruiting - verified September 2012

    A Study to Evaluate the Safety and Effect of Co-administration of ABT-450 With Ritonavir (ABT-450/r) and ABT-267 in Adults With Chronic Hepatitis C Virus Infection 
    ‎Wednesday, ‎September ‎12, ‎2012, ‏‎9:00:00 AM
    Condition: Hepatitis C Virus
    Interventions: Drug: ABT-450/r; Drug: ABT-267
    Sponsors: Abbott; Abbott
    Recruiting - verified September 2012

    Study to Investigate GS-7977 and Ribavirin for 24 Weeks in Subjects With Recurrent Chronic HCV Post Liver Transplant 
    ‎Wednesday, ‎September ‎12, ‎2012, ‏‎9:00:00 AM
    Conditions: Recurrent Chronic Hepatitis C Virus; Post Liver Transplant
    Interventions: Drug: GS-7977; Drug: Ribavirin
    Sponsors: Gilead Sciences; Gilead Sciences
    Not yet recruiting - verified September 2012

    GS-7977 and Ribavirin in Patients With Chronic HCV With Cirrhosis and Portal Hypertension With or Without Liver Decompensation 
    ‎Wednesday, ‎September ‎12, ‎2012, ‏‎9:00:00 AM
    Conditions: Hepatitis C; Cirrhosis; Portal Hypertension; With or Without Liver Decompensation
    Interventions: Drug: GS-7977; Drug: Ribavirin
    Sponsors: Gilead Sciences; Gilead Sciences
    Not yet recruiting - verified September 2012

    GS-7977 and Ribavirin in Treatment Naive and Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection 
    ‎Wednesday, ‎September ‎05, ‎2012, ‏‎9:00:00 AM
    Condition: Hepatitis C
    Interventions: Drug: GS-7977 + RBV; Drug: GS-7977 placebo + RBV placebo
    Sponsors: Gilead Sciences; Gilead Sciences
    Recruiting - verified October 2012